title: Critical proinflammatory role of thymic stromal lymphopoietin and its receptor in experimental autoimmune arthritis.
abstract: OBJECTIVE
  The interleukin-7 (IL-7)-related cytokine thymic stromal lymphopoietin (TSLP) is a potent activator of myeloid dendritic cells, enhancing Th2-mediated hypersensitivity, and it has been implicated in the pathogenesis of atopic diseases. Although intraarticular concentrations of TSLP have been shown to be increased in patients with rheumatoid arthritis (RA), the functional capacities of TSLP in arthritis are poorly studied. The purpose of this study was to investigate the effects of TSLP administration and TSLP receptor deficiency on immune activation, arthritis severity, and tissue destruction in T cell-driven arthritis models of RA.
  
  
  METHODS
  Immunopathology was studied in arthritic mice that were given multiple injections of murine recombinant TSLP and in mice that were deficient in the TSLP receptor (TSLPR(-/-)). Arthritis severity and incidence were determined by visual examination of the paws. Joint destruction was determined by assessing radiographs and the immunohistochemistry of ankle joints. Total cellularity and numbers of T cell subsets were assessed. Proinflammatory mediators were measured by multianalyte profiling of serum or paw protein extracts.
  
  
  RESULTS
  Administration of TSLP significantly exacerbated the severity of collagen-induced arthritis and the joint damage that was associated with increased T cell activation. Furthermore, TSLPR(-/-) mice had less severe arthritis than did wild-type mice. TSLPR(-/-) mice had diminished concentrations of local proinflammatory and catabolic mediators, including IL-17, IL-1β, IL-6, basic fibroblast growth factor, and matrix metalloproteinase 9, while levels of the regulatory cytokines IL-10 and IL-13 were increased.
  
  
  CONCLUSIONS
  TSLP and its receptor enhance Th17-driven arthritis and tissue destruction in experimental arthritis. The increased expression of TSLP as well as the increased number of TSLPR-expressing cells in the joints of patients with RA suggest that TSLP and its receptor constitute novel therapeutic targets in RA.
authors.affiliation: University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: S A Y
authors.initials: SA
authors.lastname: Hartgring
authors.forename: C R
authors.initials: CR
authors.lastname: Willis
authors.forename: C E
authors.initials: CE
authors.lastname: Dean
authors.forename: F
authors.initials: F
authors.lastname: Broere
authors.forename: W
authors.initials: W
authors.lastname: van Eden
authors.forename: J W J
authors.initials: JW
authors.lastname: Bijlsma
authors.forename: F P J G
authors.initials: FP
authors.lastname: Lafeber
authors.forename: J A G
authors.initials: JA
authors.lastname: van Roon
mesh_terms: D000818:Animals; D000843:Ankle Joint / Q000000981:diagnostic imaging* / Q000276:immunology / Q000378:metabolism; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D007136:Immunoglobulins / Q000276:immunology / Q000378:metabolism*; D007249:Inflammation / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism; D015851:Interleukin-7 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011859:Radiography; D018121:Receptors, Cytokine / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; D007136:Immunoglobulins; D015851:Interleukin-7; D018121:Receptors, Cytokine; C410591:Tslpr protein, mouse; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse